eHive: An Artificial Intelligence workflow system for genomic analysis

Background  

The Ensembl project produces updates to its comparative genomics resources with each of its several releases per year. During each release cycle approximately two weeks are allocated to generate all the genomic alignments and the protein homology predictions. The number of calculations required for this task grows approximately quadratically with the number of species. We currently support 50 species in Ensembl and we expect the number to continue to grow in the future.     

N-acylation of phosphatidylethanolamine and its biological functions in mammals

N-acylphosphatidylethanolamine (NAPE) and N-acylplasmenylethanolamine (pNAPE) are widely found phospholipids, and they are precursors for N-acylethanolamines, a group of compounds that has a variety of biological effects and encompasses the endocannabinoid anandamide. NAPE and pNAPE are synthesized by the transfer of an acyl chain from a donor phospholipid, to the amine in phosphatidylethanolamine or plasmenylethanolamine. NAPE has been reported to stabilize model membranes during brain ischemia, and to modulate food intake in rodents, thus having bioactive effects besides its precursor role. This paper reviews the metabolism, occurrence and assay of NAPE and pNAPE, and discusses the putative biological functions in mammals of these phospholipids. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.     

Cardiac resynchronisation therapy in patients with left bundle branch block with residual conduction

AimTo evaluate whether left bundle branch block with residual conduction (rLBBB) is associated with worse outcomes after cardiac resynchronisation therapy (CRT).MethodsAll consecutive CRT implants at our institution between 2006 and 2013 were identified from our local device registry. Pre- and post-implant patient specific data were extracted from clinical records.ResultsA total of 690 CRT implants were identified during the study period. Prior to CRT, 52.2% of patients had true left bundle branch block (LBBB), 19.1% a pacing-induced LBBB (pLBBB), 11.2% a rLBBB, 0.8% a right bundle branch block (RBBB), and 16.5% had a nonspecific intraventricular conduction delay (IVCD) electrocardiogram pattern. Mean age at implant was 67.5 years (standard deviation [SD] = 10.6), mean left ventricular ejection fraction (LV EF) was 25.7% (SD = 7.9%), and mean QRS duration was 158.4 ms (SD = 32 ms). After CRT, QRS duration was significantly reduced in the LBBB (p < 0.001), pLBBB (p < 0.001), rLBBB (p < 0.001), RBBB (p = 0.04), and IVCD groups (p = 0.03). LV EF significantly improved in the LBBB (p < 0.001), rLBBB (p = 0.002), and pLBBB (p < 0.001) groups, but the RBBB and IVCD groups showed no improvement. There was no significant difference in mortality between the LBBB and rLBBB groups. LV EF post-CRT, chronic kidney disease, hyperkalaemia, hypernatremia, and age at implant were significant predictors of mortality.ConclusionCRT in patients with rLBBB results in improved LV EF and similar mortality rates to CRT patients with complete LBBB. Predictors of mortality post-CRT include post-CRT LV EF, presence of CKD, hyperkalaemia, hypernatremia, and older age at implant.     

Enhanced sampling protocol to elucidate fusion peptide opening of SARS-CoV-2 spike protein

Large-scale conformational transitions in the spike protein S2 domain are required during host-cell infection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Although conventional molecular dynamics simulations have been extensively used to study therapeutic targets of SARS-CoV-2, it is still challenging to gain molecular insight into the key conformational changes because of the size of the spike protein and the long timescale required to capture these transitions. In this work, we have developed an efficient simulation protocol that leverages many short simulations, a dynamic selection algorithm, and Markov state models to interrogate the structural changes of the S2 domain. We discovered that the conformational flexibility of the dynamic region upstream of the fusion peptide in S2 is coupled to the proteolytic cleavage state of the spike protein. These results suggest that opening of the fusion peptide likely occurs on a submicrosecond timescale after cleavage at the S2′ site. Building on the structural and dynamical information gained to date about S2 domain dynamics, we provide proof of principle that a small molecule bound to a seam neighboring the fusion peptide can slow the opening of the fusion peptide, leading to a new inhibition strategy for experiments to confirm. In aggregate, these results will aid the development of drug cocktails to inhibit infections caused by SARS-CoV-2 and other coronaviruses.     

Changes in twelve homoeologous genomic regions in soybean following three rounds of polyploidy

With the advent of high-throughput sequencing, the availability of genomic sequence for comparative genomics is increasing exponentially. Numerous completed plant genome sequences enable characterization of patterns of the retention and evolution of genes within gene families due to multiple polyploidy events, gene loss and fractionation, and differential evolutionary pressures over time and across different gene families. In this report, we trace the changes that have occurred in 12 surviving homoeologous genomic regions from three rounds of polyploidy that contributed to the current Glycine max genome: a genome triplication before the origin of the rosids (~130 to 240 million years ago), a genome duplication early in the legumes (~58 million years ago), and a duplication in the Glycine lineage (~13 million years ago). Patterns of gene retention following the genome triplication event generally support predictions of the Gene Balance Hypothesis. Finally, we find that genes in networks with a high level of connectivity are more strongly conserved than those with low connectivity and that the enrichment of these highly connected genes in the 12 highly conserved homoeologous segments may in part explain their retention over more than 100 million years and repeated polyploidy events.     

Polymorphisms in the RNASE3 gene are associated with susceptibility to cerebral malaria in Ghanaian children

Background

Cerebral malaria (CM) is the most severe outcome of Plasmodium falciparum infection and a major cause of death in children from 2 to 4 years of age. A hospital based study in Ghana showed that P. falciparum induces eosinophilia and found a significantly higher serum level of eosinophil cationic protein (ECP) in CM patients than in uncomplicated malaria (UM) and severe malaria anemia (SA) patients. Single nucleotide polymorphisms (SNPs) have been described in the ECP encoding-gene (RNASE3) of which the c.371G>C polymorphism (rs2073342) results in an arginine to threonine amino acid substitution p.R124T in the polypeptide and abolishes the cytotoxicity of ECP. The present study aimed to investigate the potential association between polymorphisms in RNASE3 and CM.

Methodology/Principal Findings

The RNASE3 gene and flanking regions were sequenced in 206 Ghanaian children enrolled in a hospital based malaria study. An association study was carried out to assess the significance of five SNPs in CM (n = 45) and SA (n = 56) cases, respectively. The two severe case groups (CM and SA) were compared with the non-severe control group comprising children suffering from UM (n = 105). The 371G allele was significantly associated with CM (p = 0.00945, OR = 2.29, 95% CI = 1.22–4.32) but not with SA. Linkage disequilibrium analysis demonstrated significant linkage between three SNPs and the haplotype combination 371G/*16G/*94A was strongly associated with susceptibility to CM (p  = 0.000913, OR = 4.14, 95% CI = 1.79–9.56), thus, defining a risk haplotype. The RNASE3 371GG genotype was found to be under frequency-dependent selection.

Conclusions/Significance

The 371G allele of RNASE3 is associated with susceptibility to CM and forms part of a risk associated haplotype GGA defined by the markers: rs2073342 (G-allele), rs2233860 (G-allele) and rs8019343 (A-allele) respectively. Collectively, these results suggest a hitherto unrecognized role for eosinophils in CM pathogenesis.     

Comparison of two devices and two breathing patterns for exhaled breath condensate sampling

Introduction

Analysis of exhaled breath condensate (EBC) is a noninvasive method to access the epithelial lining fluid of the lungs. Due to standardization problems the method has not entered clinical practice. The aim of the study was to assess the comparability for two commercially available devices in healthy controls. In addition, we assessed different breathing patterns in healthy controls with protein markers to analyze the source of the EBC.

Methods

EBC was collected from ten subjects using the RTube and ECoScreen Turbo in a randomized crossover design, twice with every device - once in tidal breathing and once in hyperventilation. EBC conductivity, pH, surfactant protein A, Clara cell secretory protein and total protein were assessed. Bland-Altman plots were constructed to display the influence of different devices or breathing patterns and the intra-class correlation coefficient (ICC) was calculated. The volatile organic compound profile was measured using the electronic nose Cyranose 320. For the analysis of these data, the linear discriminant analysis, the Mahalanobis distances and the cross-validation values (CVV) were calculated.

Results

Neither the device nor the breathing pattern significantly altered EBC pH or conductivity. ICCs ranged from 0.61 to 0.92 demonstrating moderate to very good agreement. Protein measurements were greatly influenced by breathing pattern, the device used, and the way in which the results were reported. The electronic nose could distinguish between different breathing patterns and devices, resulting in Mahalanobis distances greater than 2 and CVVs ranging from 64% to 87%.

Conclusion

EBC pH and (to a lesser extent) EBC conductivity are stable parameters that are not influenced by either the device or the breathing patterns. Protein measurements remain uncertain due to problems of standardization. We conclude that the influence of the breathing maneuver translates into the necessity to keep the volume of ventilated air constant in further studies.     

Stock status and current tendencies in the population dynamics of commercial fishes of Pskov-Chudskoe water body

Dynamics of eight commercial populations of fish from Pskov-Chudskoe Lake forming the main bulk (up to 80%) of annual catch was analyzed using an ADAPT-VPA model making it possible to reconstruct the dynamics of the total stock biomass and fishing mortality. The populations of five species (European smelt Coregonus albula, whitefish C. lavaretus maraenoides, perch Perca fluviatilis, roach Rutilus rutilus, ruffe Gymnocephalus cernuus) in the present period demonstrate a tendency for a decrease in biomass while the stocks of two species (bream Abramis brama and zander Sander lucioperca) beginning from the 1980s considerably increased. A particularly drastic (multifold) increase in biomass is recorded in zander population. The causes of the observed population changes are related mainly to ecosystemic transformations taking place in the water body; only with respect to two species-perch and roach-can one state that the decrease in stocks is determined in part by the fishery impact. The increase in zander population is, in all probability, the result of the combined effects of eutrophication forming favorable conditions for the feeding and survival of its juveniles and fishery that led to the decrease in the biomass of one of its main food competitors-perch. The drastic increase in zander numbers in turn promoted the decrease in the biomass of species being objects of its feeding.